CORONARY ARTERY DISEASE ThC JANUARY 1, 1990, VOL. 65, NO. 1

Dyslipidemias with Desirable Plasma Total Cholesterol Levels and Angiographically Demonstrated Coronary Artery Disease

Michael Miller, MD, Lucy A. Mead, SCM, Peter 0. Kwiterovich, Jr., MD, and Thomas A. Pearson, MD, PhD

TheNatbnalchobstdEducrtson Programtreat- mentgubhesckfineapiasmatotalchokrtsrdof <200 mg/d as 9bsirabb” Cmd recommend no fur- therevahmtbnofpbsmalipidorMpoproMnbvels in patbnts with coronary artmy dsease (CAD). To Mermim!the~vclknceofdys@kbmiiinthe ~ofcoexistentCADcunltotalchobsbrd 200 mg/d, a vdwpedive case-centrd study of 1,ompatimtswlboundsment~cor~ aI@gr@ywasperfamd.of3!51~with total chdehd 200 mg,‘d, 76% of ths men (244) and 44% of the w-(107) had al&o-’ grapNuny demomtrated CAD. In men with CAD altdtotalthobsbdlzoomg/d,therewasaslg- rdik&ly~tefprevabnceofbwbvdsofhigh

llmmMn (HDL) cholerterd (535 m&II), age >SO years, systemk hypMe&on and &abetes nditus compamd to non-CAD control subjects. In womem with CAD and total chdesterd GO0 mg/ d, HDL choksterd 545 mg/dl and &betas mdl- tUSWWe8lSO d&fkmUy prevalent. Multipb bgis- tk regmdon analyses reveabd that HDL chdes-

iYlizg= andageinmsnandverybw chbstedinwonlenweresip-

niflevrtlyam withCADafteradjMmeMfor othsrriskfactors.Thesere&tssuggestthata comfWelipidandUpoprotdnanalysisbeoMainsd inaUpatbntswithCAD,hrespectiveofthsplasma (or senlm) totd clnlbad bvd.

(AmJCardbl1990;65:1-5)

From the Lipid Research Atherosclerosis Unit, Departments of Pediat- rics and Medicine, the Johns Hopkins University School of Medicine, Baltimore, Mary!and. This study was supported in part by the Preven- tive Cardiology Academic Award to Dr. Pearson (5K07HL01113) and a National Research Scientific Academy Fellowship award to Dr. Miller (5F32HM7596). Manuscript received June 1, 1989; revised manuscript received and accepted August 23, 1989.

Dr. Pearson’s present address: the Research Institute of the Mary lmogene Bassett Hospital. Cooperstown, New York.

Address for reprints: Michael Miller, MD, Division of Cardiology, Carnegie 568, the Johns Hopkins Hospital, Baltimore, Maryland 21205.

T he National Cholesterol Education Program treat- ment guidelines recommend that all adults with plasma total cholesterol levels >240 mg/dl un-

dergo lipoprotein analysis,’ because high levels of total cholesterol or low density lipoprotein (LDL) cholesterol are associated with an increased risk of coronary artery disease (CAD) and reduction of these levels decreases coronary events2 These guidelines also apply for a total cholesterol between 200 and 239 mg/dl if CAD or L2 risk factors for CAD are present. Conversely, a total cholesterol <200 mg/dl is “desirable” and no further lipid or lipoprotein analysis is recommended except for repeat total cholesterol measurements every 5 years.

High density lipoprotein (HDL) cholesterol has re- ceived less attention than LDL cholesterol, despite being a strong and independent predictor of CAD.3 Whether very low density lipoprotein (VLDL) choles- terol, or its predominant lipid, triglyceride, independent- ly predicts CAD has been controversiaL4

Because the overwhelming majority of lipid or lipo- protein abnormalities (dyslipidemias) coincide with a total cholesterol >200 mg/dl, it is not surprising that data are lacking in CAD subjects with total cholesterol 1200 mg/dl. We examine this issue.

METHODS Patient rekctkn: One thousand men and women

aged from 26 to 77 years underwent diagnostic coro- nary arteriography at the Johns Hopkins Hospital be- tween 1975 and 1978. The study population comprised 2 groups: the first consisted of 260 nonconsecutive pa- tients who had arteriograms from April 1975 to March 1977 as part of a pilot study to examine risk factors for CAD. The second group consisted of 740 consecutive patients studied from March 1977 to April 1978. The grcups differed in 2 ways. Although selection criteria were the same for groups 1 and 2, only a fraction of eligible patients were included in group 1, whereas all patients were enrolled in group 2. To test for selection bias, groups 1 and 2 were compared with regard to age, sex, race, number of diseased coronary vessels and car- diac history. The significance of differences was tested using the chi-square test. Group 1 had significantly

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 1. 1990 1

TABLE I Mean Levels of Plasma Lipids and Lipoproteins With or Without CAD and Total Cholesterol 1200 mg/dl by Sex

Men Women

CAD No CAD CAD No CAD

No. Mean f SD No. Mean f SD No. Mean f SD No. Mean f SD

Age W9 139 56f9’ 55 49f 11 37 56flO 57 52f9 TC (mg/dl) 139 175* 20. 55 167 i 25 37 176 f 23 57 169 f 26 TG bw/dl) 139 123 f 62* 55 97 l 73 37 126f61+ 57 85i37 HDL (w/d0 138 34*9* 55 4Of15 37 39flO’ 56 45f12 LDL (mg/dl) 126 119 f 22’ 53 llOf21 35 113f25 51 112f26 VLDL (mg/dl) 120 23 f 14’ 50 la*15 34 22 f 13’ 49 12f6 TC:HDL 138 6 f 2’ 55 5f2 37 5fl’ 56 4fl LDL:HDL 126 4f2’ 53 3fl 35 3fl 51 3fl

l p <o.Ds: ’ p <O.ool. CAD- u~ooary artery disease: HDL - h@ demrty Irpoprotem: LDL - low densty lipoprotein: SD - standard denat’m: TC - total chokstwd: TG = trlglycendes: VLDL = very low

d!mlly Ilpoproten. I. J

more patients (p <0.05) who were <50 years old (43 vs 35%) and black (11 vs 7%). However, groups 1 and 2 did not differ by sex (67% were men), presence of angi- na or history of myocardial infarction. Most important- ly, the 2 groups were very similar with respect to the presence or extent of CAD. We therefore combined groups 1 and 2 in the analysis.

Coranvr rteriogrrphy: After cardiac catheteriza- tion, each angiogram was reviewed by 3 cardiologists who were blinded to patient identity and tbe initial an- giographic report. There was an 88 to 95% agreement between this panel and the catheterization report. The location and severity of disease (as percent of luminal narrowing) was recorded in 15 segments of the 3 main coronary arteries and the left main coronary artery as previously describeds Patients with a luminal diameter reduction of 250% of any coronary artery segment were classified as having angiographically demonstrated CAD.

upkl d -toin uulyrk: Plasma lipid and li- poprotein levels were determined at the Johns Hopkins Lipid Research Clinic, a laboratory standardized by the Centers for Disease Control. On the morning of arteri- ography after an overnight fast, 15 ml of venous blood was collected in a single vacutainer tube containing di- sodium ethylenediaminetetraacetic acid. Plasma choles- terol and triglyceride levels were measured with a Tech- nicon Auto Analyzer II (Tecbnicon Instrument Corp.), using modified Lieberman-Burcbard and fluorometric techniques, respectively. HDL cholesterol was deter- mined after precipitation of the apo-B containing lipo- proteins in plasma with heparin-manganese. Plasma (5 ml at its own density) was subjected to ultracentrifuga- tion at 105,000 g for 18 hours; VLDL cholesterol and LDL cholesterol were determined using methods of the Lipid Research Clinics Program.6 Ultracentrifugation was performed in 87% of men and 85% of women. In tbe remaining cases, LDL cholesterol was estimated from the Friedewald formula’ (neither chylomi- cronemia nor triglycerides >400 mg/dl was present). Agarose gel electrophoresis was used to detect the pres- ence of floating /3 lipoproteins in the d < 1.006 ultracen- trifugal supematant indicative of type III byperlipopro- teinemia (dysbetalipoproteinemia), or of sinking pre-/3

2 THE AMERICAN JOURNAL OF CAROIOLOGY VOLUME 65

lipoproteins [LP(a)] in the d >1.006 ultracentrifugal infranate. The average threshold for detectability of Lp(a) is 21 mg/dl.8 Of the 1,000 patients, approximate- ly 6% did not have lipid analyses performed, primarily because heparin had been administered before sam- pling.

Lipoprotein levels were categorized for univariate analyses based on current National Cholesterol Educa- tion Program guidelines. Tbe cutoff levels were total cholesterol of 200 mg/dl, LDL cholesterol of 130 mg/dl and HDL cholesterol of 35 mg/dl. An HDL cholesterol of 45 mg/dl was also tested in woman because this rep- resents the bottom quartile and more closely approxi- mates the 35 mg/dl cutoff level in men.9 Because cri- teria for “desirable” triglyceride levels are not well established, we arbitrarily chose 150 mg/dl, which ap proximates the 50th to 75th percentile in adult men and the 75th to 90th percentile in women.9 Lipoprotein phe- notypes based on the Fredrickson-Levy classification10 were also determined.

WI hetar assamenk Risk factor assessment was determined by self-administered questionnaires and medical record review. They included: age (>50 years in men and >60 years in women), a family history of at least 1 first-degree relative with known coronary dis- ease, current smoking history (11 cigarette smoked/ day), physical activity (participant in a regular exercise program),” body mass index (weight [in kg] divided by height [in m2] on admission, with obesity defined as >27),i2 hypertension (>140/90 mm Hg at admission or while receiving antihypertensive medication), alcohol consumption (>l drink/day), diabetes mellitus (by bis- tory, use of hypoglycemic agents or fasting blood sugar > 115 mg/dl on admission). The medication status of all subjects was also recorded.

Stistkal wdr: Patients were grouped into those with and without CAD. Tbe differences in contin- uous risk factor variables between these groups were evaluated using the t test. The differences in categorical variables were measured using cbi-square tests. The designated level of significance was 0.05. Multiple logis- tic regression analysis evaluated the effects of risk fac- tors on the occurrence of CAD. The significance of the coefficients was tested using the Wald statistic. All

analyses were stratified by sex and total cholesterol level (5200 and >200 mg/d’) I using the Statistical Analysis System computer program.

RESULTS One thousand patients undergoing diagnostic coro-

nary angiography were subdivided into 2 groups: desir- able total cholesterol levels (1200 mg/dl) and border- line or high levels (>200 mg/dl). There were 935 pa- tients who had lipid analyses performed; 351 had total cholesterol 1200 mg/dl. Of 244 men and 107 women with total cholesterol 1200 mg/dl, CAD was present in 76% of men and 44% of women (p <O.Ol); the distribu- tion of CAD by gender was similar to the total choles- terol >200 mg/dl group (88% of men, 51% of women). The prevalence of CAD in whites and blacks with total cholesterol 5200 mg/dl (67 vs 59%) and >200 mg/dl (78 vs 73%) was not significantly different.

The subsequent series of data analyses focused ex- clusively on the group with total cholesterol 1200 mg/ dl. Patients (50 men, 13 women) with a recent myocar- dial infarction (<2 months) were excluded, because li- poprotein levels are altered during this period.‘) Table I lists the significant differences in mean ages, lipid and lipoprotein levels between CAD and non-CAD men. In women, only mean triglycerides, VLDL cholesterol and HDL cholesterol levels were statistically different. Mean ratios of total cholesterol to HDL cholesterol were also significantly higher in men and women with CAD.

Table II lists results of univariate analysis for the risk factors studied. Older age, systemic hypertension (in men) and diabetes mellitus (in both sexes) were sig- nificantly prevalent in CAD subjects with desirable to-

TABLE II Prevalence of Selected Risk Factors In Men and Women With or Without CAD and Total Cholesterol 5200

Family hlstory (+) 122 Cigarette smoker 133 Hypertension 138

&e 139 Exercise 121 Alcohol 122 Body mass Index >27 122 Diabetes mellltus 137 Lp(a) posltlve 117

~- No. % No. % No. % No. %

48 73 54 48 57 26 57 21 49 31 48 15 42 21 57 4 47 4

66 82 44’ 71’ 28 24 25 14’ 3

46 50 33 79 51 71 35 57 55 24 36 44 55 44 37 35 46 24 33 21 46 24 33 6 49 31 29 24 54 2 37 27’ 48 4 30 17

-7p<005.'p<0001 CAD = ~oronntv arter, dwaw

tal cholesterol levels. Figure 1 shows the significant prevalence of low HDL cholesterol in men and women with CAD. Approximately 67% of men with CAD and 33% of women with CAD had HDL cholesterol 135 mg/dl, and 80% of women with CAD had HDL choles- terol 545 mg/dl. No significant differences in preva- lence of high LDL cholesterol or triglycerides were not- ed.

There were 24 patients meeting the criteria of the Fredrickson-Levy classification; 20 men and 4 women had type IV lipoprotein patterns. Chylomicronemia was not detected in the plasma samples analyzed.

Pharmaceuticals that may impact adversely on plas- ma lipids and lipoproteins include /3 blockers and thia-

MALES FEMALES 100

iii . 60

r 60 E "' 40

g 20 a P

High Triglyceride

CA0 No CAD CAD No CA0 CAD No CAD

THE AMERICAN JOURNAL OF CARDIOLOGY JANUARY 1. 1990 3

TABI& III Mean Lipid and Lipoprotein Levels in CAD Subjects With or Without fl Blockers or Thiazide Diuretics and Total Cholesterol 1200 mg/dl

Men Women

With Without With WIthout

No. Mean f SD No. Mean f SD No. Mean f SD No. Mean f SD

f3 Blodters HDL 67 34i9 70 33 f 8 17 37 f 10 20 41 f 10 LDL 59 119f21 66 118f23 17 112f21 18 113f28 TG 67 133 f 62 71 114f62 17 149 f 77’ 20 105 f 32

Thiazide Diuretics HDL 20 31 f5 89 34f8 6 44f7 15 39flO LDL 19 129 f 18* 80 118f22 4 116f 15 15 119f 18 TG 21 122f61 89 133 f 65 6 104f26 15 133f63

l p <0.05.

Abbreviations as 8” Table I

TABLE IV Multiple Logistic Regression Analysis of CAD with Selected Risk Factors and Total Cholesterol 300 mg/dl

Men (n = 150)

Variable Coe+ficient SE

Age 0.0710 0.0221 VLDL 0.0223 0.0160 HDL -0.0518 0.0218 Hypertension 1.3412 0.4979 Body mass index -0.0810 0.0532

NS - not s&cant: SE = stmcbrd e,rw. Other abbrewatms as I” Table I

p Value

0.001 NS 0.018 0.007 NS

Women (n = 64)

Coefficient

o.Ow2 0.1736 0.0053 0.3032

-0.0656

SE p Value

0.0340 NS 0.0551 0.002 0.0309 NS 0.6805 NS 0.0703 NS

zide diuretics.t4 Although 49% of men with CAD (137) and 46% of women with CAD (37) were receiving p blockers, the prevalence of low HDL cholesterol (135) was not significantly different between the @-blocker and non-&blocker groups (66 vs 7 1% in men; 41 vs 25% in women). Mean lipid and lipoprotein levels in CAD subjects with or without P-blocker or thiazide use is list- ed in Table III. Significantly higher mean LDL choles- terol in men, and triglycerides in women, accompanied thiazide and &blocker use, respectively. Mean HDL cholesterol levels were not significantly altered with use of either drug. Furthermore, mean HDL cholesterol in CAD subjects receiving /3 blockers was not statistically different than in the non-CAD control subjects (34 vs 36 mg/dl in men; 41 vs 43 mg/dl in women). In addi- tion to these drugs, 8 women were using estrogen sup plements or oral contraceptives and 5 men were receiv- ing clofibrate for hypertriglyceridemia.

A multiple logistic regression model of CAD was constructed using age, HDL cholesterol, VLDL choles- terol, body mass index and hypertension (Table IV) as the independent variables. Diabetes mellitus was not added to the model due to the small number of diabetic subjects without CAD (1 man and 2 women). In men, age, plasma HDL cholesterol and hypertension were in- dependently correlated with CAD. In women, VLDL cholesterol was the sole variable independently associ- ated with CAD, after adjustment for other risk factors. The addition of #I blockers to the model did not alter the significant independent effect of HDL cholesterol in men (p = 0.02) or VLDL cholesterol in women (p = 0.002).

4 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

DISCUSWON The National Cholesterol Education Program re-

cently established guidelines for the detection and man- agement of hyperlipidemia and is predicated on the re- sults of a screening of total cholesterol. If a total choles- terol level is <200 mg/dl, reassurance is provided and cholesterol measurements need not be repeated for up to 5 years thereafter. There is no allowance for lipid or lipoprotein analysis. Hence, atherogenic dyslipidemias present despite desirable cholesterol levels will not be detected under the current system.

Although the incidence of CAD increases considera- bly as cholesterol levels increase >200 mg/dl,l evidence that a desirable total cholesterol does not afford immu- nity from CAD is exemplified in the Framingham Study, where >15% of middle-aged adults developing CAD over a 12-year period had total cholesterol levels <200 mg/dl.15 The high prevalence of desirable choles- terol levels (34%) among CAD patients in the present study is noteworthy; despite these levels, HDL choles- terol was independently associated with CAD in men, even after adjustment for other confounding variables (i.e., p blockers).

That low levels of HDL cholesterol predict CAD is well documented in hyperlipidemic patientsI Results from long-term prospective studies”*‘* now support similar conclusions even when cholesterol levels are not elevated. Our data provide further evidence that a total cholesterol in the desirable range may underestimate the importance of HDL cholesterol.

The role of VLDL cholesterol (or triglycerides) as an independent predictor of coronary disease remains

unresolved, although it has been demonstrated in wom- en and men aged >50 years.19 Recently, triglycerides were a significant predictor of coronary death when to- tal cholesterol levels were <220 mg/dl; several potential mechanisms have been postulated.20 In the present study, VLDL cholesterol was the only independent vari- able associated with CAD in women. Mean triglyceride levels were also significantly higher in both men and women with CAD (Table II) than in non-CAD pa- tients. Normal or mildly elevated plasma triglycerides (150 to 250 mg/dl) often occur in hyperapob-etalipo- proteinemia (hyperapoB), a lipid disorder marked by in- creased levels of the major apolipoprotein of LDL, apo B, and an increased risk of CAD in the presence of a normal or near-normal LDL cholesterol.2’ Apolipopro- teins were not measured in this study and consequently, the prevalence of this disorder could not be ascertained.

Identification of low HDL cholesterol or high tri- glyceride levels in CAD patients is warranted because they may be potentially modifiable through smoking cessation,22 aerobic exercise,23 weight reduction, fat- modified diets and drugs. Dietary restriction decreases triglyceride and increases HDL cholesterol levels in obese subjects.’ Unfortunately, there are no unique HDL cholesterol-raising diets; the objective therefore, is to improve the total or LDL cholesterol to HDL choles- terol ratio by substituting poly- or monounsaturated for saturated fats.24

Pharmaceuticals may be tried if traditional mea- sures fail. Elevations in HDL cholesterol up to 37% and reductions in triglycerides by 40?& have been achieved with these agents.2sv26 More importantly, dietary or pharmacologic manipulation, which significantly in- crease HDL cholesterol while decreasing LDL choles- terol or triglycerides, may halt progression of existing atherosclerotic lesions,27*2x even in the setting of a “de- sirable” total cholesterol.26 This is of considerable sig- nificance for men with CAD, in whom, even in the pres- ence of desirable cholesterol levels, the incidence of fur- ther coronary events (myocardial infarction or sudden death) is nearly 9-fold greater than for men without CAD.29

It has recently been demonstrated that increasing HDL cholesterol independently reduces future CAD events in hyperlipidemic subjects.3o Whether the same is applicable in subjects with isolated low HDL choles- terol levels but desirable total cholesterol levels is an area that merits further investigation. Presently, we be- lieve that secondary preventive measures should be maximized in all CAD subjects, and therefore complete lipid and lipoprotein analysis should be made a routine part of this approach.

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